This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose to examine whether sleep problems in children with autism spectrum disorder (ASD) are related to alterations in the secretion of melatonin (MT), a hormone that plays an important role in regulating the circadian cycle and sleep. Furthermore, we will examine the efficacy of MT for improving sleep in children with ASD. Children with ASD experience high rates of sleep disturbances that potentially contribute to the severity of their cognitive and behavioral dysfunction and to poor quality of life for themselves and their families. It is unclear if irregularities in MT rhythm underlie sleep problems in children with ASD. Their sleep problems are characterized by sleep-wake rhythm abnormalities and symptoms of insomnia including difficulty initiating and maintaining sleep. MT is frequently used to treat these sleep problems;however, its effectiveness as a hypnotic to treat insomnia in children with ASD has not been clearly established. All subjects will be recruited from the Autism Treatment Network after completing rigorous diagnostic testing. Exclusionary criteria include exposure to melatonin in the month prior to the study, current psychoactive medications or medications known to suppress MT secretion, other sleep disorders, such as sleep apnea, and medical disorders that may affect sleep, such as gastroesophageal reflux disease (GERD). Participants'parents will complete a validated sleep questionnaire, which will define the presence or absence of sleep problems. MT onset will be determined by measuring salivary MT levels before and after usual bedtime in ASD children with sleep problems and in a matched group of children with ASD and no sleep problems. Total 24 hour MT production will be determined from urine samples in these same two groups. A double-blind, randomized trial of three oral doses of MT (3, 6, 9 mg) and placebo in children (ages 4-9 years) with ASD and sleep problems will follow a baseline sleep and behavior evaluation. The primary outcome measure will be change in sleep latency as determined by actigraphy at baseline and at the end of the fifth week of each of the treatment trials. Another primary outcome measure will be change in validated behavioral questions given at baseline and during the fifth week of each of the treatment trials. Results from this study will provide a rationale for the development of future trials of circadian rhythm interventions and clinical parameters for the use of MT to manage sleep problems in ASD. Our hypotheses concerning MT are: 1. Children with ASD and sleep problems will have a delay in MT onset and/or have decreased MT secretion over 24 hours;2. Oral MT will be associated with improvement in sleep and behavior in children with ASD and sleep problems. SPECIFIC AIMS: This is a proposal to study the relationship between melatonin (MT) and sleep problems in children with autism spectrum disorder (ASD), as part of the collaborative research structure of the Autism Treatment Network (ATN). A major goal of the ATN is to conduct clinical research that will have a significant impact on the daily lives and functioning of individuals with ASD and to address immediate concerns of parents. Children with ASD experience high rates of sleep disturbance, which likely contribute to the severity of their daytime cognitive and behavioral dysfunction and to poorer quality of life for them and their families. As a step toward addressing sleep problems in ASD, we propose to test two hypotheses. Our first hypothesis proposes that children with ASD and sleep problems will have a delay in MT onset and/or have decreased MT secretion over 24 hours. Our second hypothesis proposes that administration of exogenous MT will result in a decrease in sleep problems and a subsequent improvement in daytime behaviors, with higher doses showing greater effect. This research project has the following specific aims: Specific Aim 1: Characterize the endogenous MT profiles in children with ASD with and without sleep problems. Specific Aim 2: Determine the efficacy of MT used as a hypnotic for improving sleep directly and secondarily improving daytime behavior in children with ASD and sleep problems. We predict that results from this study will reveal lower levels of metabolized MT in children with ASD and sleep problems when compared to ASD children without sleep problems. In addition, we anticipate that children with ASD and sleep problems will have delayed MT onset or altered circadian phase. We predict that participants will experience improved sleep after treatment with oral MT, as indicated by shortened sleep latency. We anticipate that children with altered circadian phase will show better response to treatment with MT. We predict that participants who experience improved sleep will demonstrate improved daytime behaviors as a result of their improved sleep. Data from this study will provide important information concerning circadian rhythm dysregulation in ASD and will support the development of future studies using MT to modify and correct abnormal circadian rhythms.